Three major families of antitumor agents are known. Each of the families of agents is associated with a recognized mechanism of action. First, antitumor agents may be alkylating agents, which generally bind in a covalent manner with DNA to form bifunctional lesions. The bifunctional lesions involve adjacent or nearby bases on the same strand, or alternatively, involve bases on opposite strands forming interstrand crosslinks. Second, antitumor agents may be antimetabolites, which generally inhibit enzymes involved in the synthesis or assembly of DNA. Alternatively, an antimetabolite may serve as a fraudulent or analog substrate of DNA processes. Third, antitumor agents may be antibiotics, which work by intercalating into the DNA helix or introducing strand breaks into DNA.
Thousands of potential anticancer agents have been evaluated. Essentially, all effective agents (of which very few have been found) appear to work by one of the above-mentioned mechanisms. The subject invention concerns a class of molecules which are not associated with any of the three major families of antitumor agents.
Proteases are ubiquitous enzymes involved in a myriad of cellular activities including digestion, blood coagulation and fibrinolysis, the processing and degradation of proteins, sperm penetration, and have been implicated as important components in regulating cascades.
Proteases and protease inhibitors have been reported in association with cancer-related processes. The most common associations involve increased protease enzyme activities or enzyme concentration. Such increased protease activity may be associated with transformation of cells by viruses, chemicals or other agents, as well as with the metastatic potential of cancer cells. Additionally, data have been published which suggest that protease inhibitors may prevent or reduce the incidence of transformation and reduce the metastatic potential of cancer cells. A number of protease inhibitors has been previously evaluated against murine tumor cells in both culture and in whole animals as potential antitumor agents. Reports exist of modest growth inhibition of cells in culture following exposure to protease inhibitors, such as chloromethyl ketones, soybean trypsin inhibitor, ovomucoid, and aprotinin. Most are inert or require very high concentrations to achieve significant tumor cell killing.
The synthesis and protease inhibition properties of a number of dipeptide analogs, including Cbz-ala-1-borovaline and Cbz-ala-1-borophenylalanine, wherein Cbz is an abbreviation for the benzyloxycarbonyl protecting group, and Ala is the abbreviation for the alanyl peptidyl residue, have been previously reported (D. H. Kinder et al., J. Med. Chem., 28, 1917 (1985). The structures of these two analogs are depicted in FIG. 1. One of the analogs, Cbz-ala-1-borophenylalanine, has also been evaluated for its ability to inhibit cultured human nasopharyngeal carcinoma cells and Lewis lung murine tumor cells (Goz et al., Biochem. Pharmacol., 35, 3587 (1986)).
The synthetic route employed by D. H. Kinder et al. was based on the route disclosed by D. Matteson et al. J. Amer. Chem. Soc., 103, 5241 (1981) for the synthesis of (R)-1-acetamido-2-phenylethaneboronic acid. The synthetic route can be summarized as shown in Scheme 1, hereinbelow: ##STR2## When, for example, R.sup.1 is Cbz-ala, compound 1' is Cbz-ala-1-borophenylalanine.
A. B. Shenvi et al. (U.S. Pat. No. 4,499,082) discloses tri- and tetrapeptide analogs of the general formula: ##STR3## wherein A.sup.1, A.sup.2 and A.sup.3 are amino acid residues, n is 1 and o is 0 or 1, Y.sup.1 and Y.sup.2 are each H, or represent a divalent protecting group, R.sup.2 is, e.g., alkyl or aralkyl and R.sup.1 is H or an N-terminal protecting group such as Cbz. Specific tripeptide analogs are the subject of Examples 11, 16-19 and 22 of this patent. These .alpha.-aminoboronic acid peptides are disclosed to be useful as inhibitors of metallo, acid, and serine proteases. Suggested therapeutic uses for these compounds include the treatment of emphysema. A. B. Shenvi (U.S. Pat. No. 4,537,773) generally discloses and claims compounds of formulas 2 and 3 as depicted in Scheme I, hereinabove, e.g., wherein the benzyl substituent has been replaced by lower alkyl.
However, a need exists for new synthetic routes to boronic acid peptides. A further need exists for new therapeutic uses of boronic acid peptides.